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Effects of branching architecture and linker on the activity of hyperbranched polymer-drug conjugates.

ABSTRACT: Drug release from hyperbranched polymer-drug conjugates and the subsequent activity are influenced by the branching architecture and the linker. To gain an understanding of these effects, we used hyperbranched polyol and G4-OH polyamidoamine (PAMAM) dendrimer with methyl prednisolone (MP) as the model drug. The drug was conjugated to dendrimer or polyol using a glutaric acid (GA) or a succinic acid (SA) spacer. Drug payload was the highest with polyol, while in the case of dendrimer, a higher payload was achieved with the GA than the SA spacer. Cell uptake of the polymer conjugates in A549 lung epithelial cells was higher than that of the free drug, and the conjugates largely localized in the cytosol. The anti-inflammatory activity of polymer conjugated MP, as measured by inhibition of prostaglandin synthesis, was the highest for MP-SA-dendrimer conjugate, followed by MP-GA-polyol conjugate, and then MP-GA-dendrimer conjugate. This study suggests that the branching architecture and spacer influence the drug payload and pharmacological activity of a drug-nanopolymer conjugate, which may significantly influence the in vivo efficacy of these nanodevices. This has key implications in the eventual in vivo efficacy of these nanodevices.

SUBMITTER: Perumal O

PROVIDER: S-EPMC2885566 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Effects of branching architecture and linker on the activity of hyperbranched polymer-drug conjugates.

Perumal Omathanu O Khandare Jayant J Kolhe Parag P Kannan Sujatha S Lieh-Lai Mary M Kannan Rangaramanujam M RM

Bioconjugate chemistry 20090501 5

Drug release from hyperbranched polymer-drug conjugates and the subsequent activity are influenced by the branching architecture and the linker. To gain an understanding of these effects, we used hyperbranched polyol and G4-OH polyamidoamine (PAMAM) dendrimer with methyl prednisolone (MP) as the model drug. The drug was conjugated to dendrimer or polyol using a glutaric acid (GA) or a succinic acid (SA) spacer. Drug payload was the highest with polyol, while in the case of dendrimer, a higher pa ...[more]

PMID: 19402625

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Project description:Charge variants are important attributes of monoclonal antibodies, including antibody-drug conjugates (ADCs), because charge variants can potentially influence the stability and biological activity of these molecules. Ion exchange chromatography (IEX) is widely used for charge variants analysis of mAbs and offers the feasibility of fractionation for in-depth characterization. However, the conjugated linker-drug on ADCs could potentially affect the separation performance of IEX, considering IEX separation relies on surface charge distribution of analyte and involves the interaction between analyte surface and IEX stationary phase. Here, we investigated weak cation exchange chromatography (WCX) for its application in analyzing three ADCs (two broad distribution ADCs and an ADC with controlled conjugation sites) and the 2-drug/4-drug loaded species isolated from the two broad distribution ADCs using hydrophobic interaction chromatography. The major peaks in WCX profile were characterized via fraction collection followed by capillary electrophoresis-sodium dodecyl sulfate or peptide mapping. Results suggested that both the number of drug loads and conjugation sites could impact WCX separation of an ADC. The hypothesis was that the linker drugs could interfere with the ionic interaction between its surrounding amino acids on the mAb surface and column resin, which reduced the retention of ADCs on WCX column in this study. Our results further revealed that WCX brings good selectivity towards positional isomers, but limited resolution for different drug load, which causes the peak compositions of the two broad-distribution ADCs to be highly complex. We also compared results from WCX and imaged capillary isoelectric focusing (icIEF). Results showed that separation in icIEF was less influenced by conjugated linker drugs for the ADCs studied in this work, and better alignment was found between the two techniques for the ADC with controlled conjugate sites. Overall, this work provides insights into the complexity of WCX analysis of ADCs, which should be considered during method development and sample characterization.

Dataset Information

Effects of branching architecture and linker on the activity of hyperbranched polymer-drug conjugates.

Publications

Effects of branching architecture and linker on the activity of hyperbranched polymer-drug conjugates.

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